Epromoters function as a hub to recruit key transcription factors required for the inflammatory response

• Published in: Nature communications 2021-11, Vol.12 (1), p.6660-18, Article 6660
• Main Authors: Santiago-Algarra, David, Souaid, Charbel, Singh, Himanshu, Dao, Lan T. M., Hussain, Saadat, Medina-Rivera, Alejandra, Ramirez-Navarro, Lucia, Castro-Mondragon, Jaime A., Sadouni, Nori, Charbonnier, Guillaume, Spicuglia, Salvatore
• Format: Article
• Language: English
• Subjects: 38/70; 45/77; 49/15; 49/39; 49/47; 631/208/200; 631/250/256; Animals; Biochemistry, Molecular Biology; Enhancer Elements, Genetic - drug effects; Enhancer Elements, Genetic - physiology; Enhancers; Gene clusters; Gene expression; Gene Expression Regulation; Genes; Genomics; HeLa Cells; Humanities and Social Sciences; Humans; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammatory response; Interferon; Interferon Regulatory Factors - metabolism; Interferon Type I - metabolism; Interferon-alpha - pharmacology; K562 Cells; Life Sciences; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - drug effects; Mice; multidisciplinary; Multigene Family - drug effects; Multigene Family - genetics; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - physiology; Promoters; Regulatory sequences; Science; Science (multidisciplinary); Stat1 protein; STAT1 Transcription Factor - metabolism; STAT2 Transcription Factor - metabolism; Transcription activation; Transcription factors; α-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26861-0

Gene expression is controlled by the involvement of gene-proximal (promoters) and distal (enhancers) regulatory elements. Our previous results demonstrated that a subset of gene promoters, termed Epromoters, work as bona fide enhancers and regulate distal gene expression. Here, we hypothesized that Epromoters play a key role in the coordination of rapid gene induction during the inflammatory response. Using a high-throughput reporter assay we explored the function of Epromoters in response to type I interferon. We find that clusters of IFNa-induced genes are frequently associated with Epromoters and that these regulatory elements preferentially recruit the STAT1/2 and IRF transcription factors and distally regulate the activation of interferon-response genes. Consistently, we identified and validated the involvement of Epromoter-containing clusters in the regulation of LPS-stimulated macrophages. Our findings suggest that Epromoters function as a local hub recruiting the key TFs required for coordinated regulation of gene clusters during the inflammatory response. Some promoters, termed Epromoters, can display enhancer activity and regulate distal genes in their endogenous context. Here the authors report the broad involvement of Epromoters in the coordinated activation of interferon (IFN) response. They show activation of a number of IFN-inducible genes is a result of Epromoters regulating expression of an entire IFN response gene cluster.